A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-440 Combination Therapy in Subjects Aged 12 Years and Older With Cystic Fibrosis
- CTRC Outpatient
- Children’s Medical Center (Dallas, Plano, Southlake)
- Clements University Hospital
- UT Southwestern Ambulatory Services
Raksha Jain, M.D.
This is a Phase 2, randomized, double-blind, placebo- and TeZ/iVa-controlled, parallel group, multicenter study. The treatment arms and doses of VX-440, TeZ, and iVa to be evaluated are shown in the table on page 7 of the protocol.
Part 1 will consist of 2 cohorts: Cohort 1a and Cohort 1B. The start of dosing of Cohort 1a and Cohort 1B will be sequential. after all Cohort 1a subjects complete the Day 15 Visit, a blinded review of all available safety and PK data will be conducted by the Vertex study team and lead investigator(s). Dosing of Cohort 1B will begin after the blinded review, if supported by safety and PK data.
Part 1 Cohort 1a: Randomization 4:1
Part 1 Cohort 1B: Randomization 2:1:1
Part 2 will initiate after the Cohort 1a blinded review, if supported by safety and PK data.
Part 3 will not be conducted.
Part 4 will only be initiated after Part 1 has been completed. inclusion of adolescent CF subjects will only occur if Part 1 safety and efficacy data support evaluation in adolescent subjects.
* Safety and tolerability assessments based on adverse events (aes), clinical laboratory values, standard 12-lead electrocardiograms (eCGs), vital signs, and pulse oximetry
* absolute change in percent predicted forced expiratory volume in 1 second (ppFeV1) from baseline through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)
* absolute change in sweat chloride concentrations from baseline through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)
* Relative change in ppFeV1 from baseline through Day 29 (Parts 1 and 2) and through Week 12 (Part 4)
* number of pulmonary exacerbations through Week 12 (Part 4)
* Time-to-first pulmonary exacerbation through Week 12 (Part 4)
* absolute change in body mass index (BMi) from baseline at Week 12 (Part 4)
* absolute change in BMi z-score from baseline at Week 12 (Part 4)
* absolute change in weight from baseline at Week 12 (Part 4)
* absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline at Day 29 (Parts 1 and 2) and at Week 12 (Part 4)
* PK parameters of VX-440, TeZ, M1-TeZ, iVa, and M1-iVa
* absolute change in CFQ-R non-respiratory domain scores from baseline at Day 29 (Parts 1 and 2) and at Week 12 (Part 4)
* absolute change in inflammatory mediators from baseline at Week 12 (Part 4)
1. Subject (or subject[Single Quote]s legally appointed and authorized representative) will sign and date an informed consent form (ICF), and, when appropriate, an assent form.
2. Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.
3. Subjects will be aged 18 years or older for Parts 1 and 2, and aged 12 years or older for Part 4, on the date of informed consent and, when appropriate, date of assent.
4. Body weight >=35 kg.
5. Sweat chloride value >=60 mmol/L from test results obtained during screening. If the value cannot be determined from the screening test, a sweat chloride value documented in the subject[Single Quote]s medical record may be used to establish eligibility. (It is acceptable to use a sweat chloride value that was obtained before previous treatment with IVA, LUM/IVA, or an investigational CFTR modulator).
6. Subjects must have an eligible CFTR genotype as noted below. If the screening CFTR genotype result is not received before randomization (Parts 1 and 4) or before Day -28 (Part 2), a previous CFTR genotype laboratory report may be used to establish eligibility. Note: Subjects who have been randomized and whose screening genotype does not confirm study eligibility must be discontinued from the study (Section 9.5).
* Part 1 and Part 4: Heterozygous for F508del with a second CFTR allele carrying an MF mutation that is not likely to respond to TEZ and/or IVA therapy (Appendix A)
* Part 2: Homozygous for F508del
7. Parts 1, 2, and 4 subjects must have an FEV1 >=40% and <=90% of predicted normal for age, sex, and height (equations of the Global Lung Function Initiative [GLI])13 at the Screening Visit. Spirometry measurements must meet American Thoracic Society/European Respiratory Society criteria10 for acceptability and repeatability.
8. Stable CF disease as judged by the investigator.
9. Willing to remain on a stable CF medication regimen through the planned end of treatment or, if applicable, the Safety Follow-up Visit.